Further characterization of the 5-HT1 receptors mediating cardiac sympatho-inhibition in pithed rats: pharmacological correlation with the 5-HT1B and 5-HT1D subtypes

Abstract

Serotonin (5-hydroxytryptamine; 5-HT) is capable of inhibiting the tachycardic responses elicited by sympathetic stimulation, but not by exogenous noradrenaline, in pithed rats pre-treated with desipramine. More recently, it has been shown that this cardiac sympatho-inhibitory response to 5-HT, mediated by prejunctional 5-HT1 receptors as well as putative 5-ht5A/5B receptors, is mimicked dose-dependently by the agonists CP 93,129 (r5-HT1B), sumatriptan (5-HT1B/1D) and PNU-142633 (5-HT1D). This study analysed further the pharmacological profile of the above 5-HT1 receptors. Continuous i.v. infusions of CP 93,129, sumatriptan or PNU-142633 (30 micro g kg(-1)min(-1) each) failed to modify the tachycardic responses to exogenous noradrenaline but inhibited those elicited by preganglionic (C7-T1) stimulation of the cardiac sympathetic outflow. These sympatho-inhibitory responses were unaltered after i.v. administration of physiological saline (1 ml kg(-1)) or the 5-HT1A receptor antagonist WAY 100635 (10 micro g kg(-1)). In contrast, the antagonist GR 127935 (5-HT1B/1D; 100 micro g kg(-1), i.v.) abolished the responses to CP 93,129, sumatriptan and PNU-142633, whilst SB224289 (5-HT1B; 300 micro g kg(-1), i.v.) abolished the responses to CP 93,129 without affecting those to sumatriptan and PNU-142633. Interestingly, BRL15572 (5-HT1D; 300 micro g kg(-1), i.v.) abolished the responses to PNU-142633 and attenuated those to sumatriptan, but not those to CP 93,129. WAY 100635, GR 127935, SB224289 and BRL15572, given alone at the above doses, failed to modify the sympathetically induced tachycardic responses. The 5-HT1 receptors producing cardiac sympatho-inhibition in pithed rats thus display the pharmacological profile of the 5-HT1B and 5-HT1D receptor subtypes.